The goal of this research is to determine the mechanisms that regulate cell and tissue responses to biomaterials that interface with bone. This proposal addresses the clinical need for dental and orthopedic implants that promote rapid osteointegration and earlier loading times, particularly when placed in bone compromised by disease or physiology of the patient. By understanding how surface morphology and chemistry modulate cell response, materials may be developed that control cell behavior through structural signaling, without the need for pharmacologic modification. We use structured surfaces as models to define which micron-, submicron-, and nanoscale features and chemistry regulate specific cell responses and to study the underlying mechanisms involved, with the long-term goal of creating rational biomimetic materials that facilitate normal tissue regeneration and repair. Our experimental hypothesis is that physical and chemical properties of a surface determine integrin expression, influencing cellular signaling and response to systemic factors that regulate osteogenesis and to autocrine and paracrine mediators of osteoblast differentiation. Moreover, changes in mesenchymal stem cells (MSCs) and osteoprogenitor cells on the substrate influence peri-implant bone formation through production of factors that modulate angiogenesis and osteogenesis. To test this hypothesis, we propose to examine osteoblast behavior in vitro and in vivo using novel materials with nanoscale features and well controlled chemistries. We will interrogate the substrate morphology and chemistry under individual cells using new imaging technology developed in our group, which permits us to identify living cells expressing specific mRNAs. We will use stably silenced cell lines that have reduced expression of specific proteins that mediate the response of osteoblasts to material surface microstructure and we will use an in vitro co-culture model as well as in vivo mouse and rat models that permit us to screen the clinical utility of the structural features identified in vitro, focusing on vasculogenesis/angiogenesis during bone healing in aged and osteopenic animals. We will (1) develop and characterize at the nanoscale, surface features and chemical functionalities that may modulate MSC differentiation and osteoblast phenotypic expression; (2) determine the mechanisms that mediate the differential effects of surface design features, including the role of integrins and Want signaling; and (3) assess how changes in surface design mediate peri- implant bone formation in vivo in aging and ovariectomized mice and rats.